The Modulation of Gamma Oscillations by Methamphetamine in Rat Hippocampal Slices

Abstract

Gamma frequency oscillations (γ, 30-100 Hz) have been suggested to underlie various cognitive and motor functions. The psychotomimetic drug methamphetamine (MA) enhances brain γ oscillations associated with changes in psychomotor state. Little is known about the cellular mechanisms of MA modulation on γ oscillations. We explored the effects of multiple intracellular kinases on MA modulation of γ induced by kainate in area CA3 of rat ventral hippocampal slices. We found that dopamine receptor type 1 and 2 (DR1 and DR2) antagonists, the serine/threonine kinase PKB/Akt inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonists prevented the enhancing effect of MA on γ oscillations, whereas none of them affected baseline γ strength. Protein kinase A, phosphoinositide 3-kinase and extracellular signal-related kinases inhibitors had no effect on MA. We propose that the DR1/DR2-Akt-NMDAR pathway plays a critical role for the MA enhancement of γ oscillations. Our study provides an new insight into the mechanisms of acute MA on MA-induced psychosis.

Keywords: Akt/PKB; DR; NMDAR; hippocampus; methamphetamine; γ oscillation.

FIGURE 1

The influence of MA on KA-induced γ oscillations. (A) Typical example of the development of γ power in hippocampal area CA3, as function of time after the start of KA (200 μM). After γ power stabilized, MA (20 μM) was added. (B) Example of γ oscillations recorded in area CA3, induced by KA and after addition of MA. (C) Power spectra of the oscillatory activity in KA alone (black line) and after MA application (red line) for the slice in B. (D) The γ power (normalized to the KA only baseline value for continued KA only application (control) and for MA application at various concentrations (^*P < 0.05; ^∗∗P < 0.01; ^∗∗∗P < 0.001). (E) Peak frequency of γ oscillations before and after MA application at various concentrations (details as in D). (F) Example of activity recorded in control aCSF and after application of MA (20 μM). (G) Power spectra of the oscillatory activity in control (black line) and after MA application (red line) for the slice in F.

FIGURE 2

SCH23390 blocked the MA-induced increase in γ oscillations. (A) Recordings from CA3 in the presence KA alone, KA + 10 μM SCH23390 (SCH) and KA + 10 μM SCH23390 + 20 μM MA. (B) The power spectra of recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA + SCH23390 and KA + SCH23390 + MA (^*P < 0.05).

FIGURE 3

Raclopride blocked the MA-induced increase in γ oscillations. (A) CA3 recordings for KA alone, KA+ 10 μM Raclopride and KA+10 μM Raclopride + 20 μM MA. (B) The power spectra of recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA + Raclopride and KA+ Raclopride + MA.

FIGURE 4

H89 does not affect the MA-induced increase in γ oscillations. (A) CA3 recordings for KA alone, KA + 10 μM H89 and KA + 10 μM H89 + 20 μM MA. (B) The power spectra of the recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA + H89, KA + H89 + MA and KA + MA (^*P < 0.05, ^∗∗P < 0.01, ns: not significant).

FIGURE 5

U0126 does not affect the MA-induced increase in γ oscillations. (A) CA3 recordings for KA alone, KA + 2.5 μM U0126 and KA + 2.5 μM U0126 + 20 μM MA. (B) The power spectra for the recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA+ U0126, KA+ U0126 + MA and KA+MA (^*P < 0.05, ns: not significant).

FIGURE 6

Wortmannin does not affect the MA-induced increase in γ oscillations. (A) CA3 recordings for KA alone, KA + 0.2 μM wortmannin (Wort) and KA + 0.2 μM wortmannin + 20 μM MA. (B) The power spectra for the recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA+ Wortmannin, KA + Wortmannin + MA and KA + MA (^*P < 0.05, ns: not significant).

FIGURE 7

Triciribine blocked the MA-induced increase in γ oscillations. (A) CA3 recordings for KA alone, KA+ 5 μM triciribine and KA+5 μM triciribine +20 μM MA. (B) The power spectra for the recordings in A. (C) γ power as percentage of preceding baseline for KA, KA + triciribine and KA + triciribine + MA and KA + MA.

FIGURE 8

D-AP5 blocked the MA-induced increase in γ oscillations. (A) CA3 recordings for the presence KA alone, KA+ 10 μM D-AP5 and KA+10 μM D-AP5 + 20 μM MA. (B) The power spectra for the recordings in A. (C) γ power as percentage of preceding baseline for KA alone, KA+ D-AP5 and KA+ D-AP5 + MA.

FIGURE 9

Diagram showing the possible mechanisms for MA-mediated enhancement ofγ oscillations. MA increases dopamine levels, which activates both DR1 and DR2 (green arrow 1, indicating activation), which causes transactivation of receptor tyrosine kinase (RTK) (2), and downstream kinase Akt phosphorylation (3). Akt activation increases postsynaptic GABA_A receptors (4) and activates NMDAR (5), which may also activate Akt (6). In addition MA can increase glutamate levels that activate NMDA receptors (7). NMDAR activation and the increased GABA_AR expression can both contribute to the enhancement of γ oscillations.